Recently, there has been a surge of interest in leveraging silicon photonics for biosensing, with the ultimate goal of producing a chip with thousands of orthogonal sensors capable of functioning in clinical environments and available at minimal cost. Silicon photonic biosensors have already achieved impressive sensitivities relevant for biomedical applications. However, the field has been stymied by the challenge of biological specificity, the ability to bind preferentially to an analyte of interest when sensing in complex biological samples (e.g., blood, plasma, serum). Here we show, for the first time on a silicon photonics platform, label-free biosensing with clinically relevant sensitivity in undiluted human serum. Utilizing a zwitterionic polymer-based surface chemistry, we dramatically limit the amount of non-specific protein adsorption to a microring resonator in serum, while maintaining a label-free sensitivity of 10 ng ml−1. This result represents a significant step towards the practical application of silicon photonics for medical diagnostics and the biomedical sciences.
The noteworthy potential of silicon photonics emerges from the combination of excellent optical devices with control electronics to produce inexpensive integrated photonics systems. In recent years, on-chip modulators, detectors, and hybrid lasers have all been demonstrated. Microring resonators are exceedingly amenable to scalable fabrication using CMOS-compatible processes, setting them apart from most other resonant optical microcavity devices for high-throughput, multiplexed biosensing. To utilize the microring resonator for biological sensing, a binding site is chemically introduced on the surface of the sensor and a shift in the resonance wavelength of the microring is observed upon analyte binding. Exploiting this approach, SOI microring resonators have been used for the detection of a diverse range of biological species, including antibodies, proteins, nucleic acids, and bacteria, among others.
In evaluating a biosensor for a given application, there are two main figures of merit. First, the sensitivity of the device, and second, the complexity of the background solution in which the assay can be performed successfully. Many recent biosensing results have yielded excellent sensitivity, but in relatively simple solutions (low biological noise). FIG. 1A shows the distribution of attained sensitivities, as well as the biological noise in each demonstration. The suitability of these platforms for use in clinical assays depends not only on their sensitivity, but also on the selectivity of these sensors for a particular analyte in complex biological fluids (solutions with high biological noise).
For comparison, FIG. 1A includes the sensitivities of both colorimetric and chemiluminescent enzyme-linked immunosorbent assay (ELISA), the standard diagnostic technique used by most hospitals. Despite its widespread use and perceived effectiveness, the ELISA method is not without its limitations, as it requires signal amplification of bound analyte by primary and labeled secondary antibodies, substantially increasing both the cost and time of the diagnostic. A competing technology to ELISA, surface plasmon resonance (SPR), has also achieved low sensitivities in complex media. However, due to the complexity of plasmonic systems integration, SPR has not been realized as a highly-parallelized, portable, low-cost clinical assay. Also, while SPR is an effective label-free biosensing technology, the sensing range of SPR is limited, due to the exponential decay of the surface plasmon from the gold substrate. Thus, SPR is poorly suited to study targets, such as bacteria, where the size of the target places the majority of the refractive index change outside of the range of the evanescent wave. Therefore it would be desirable to develop a related label-free technology that could be used to sense targets at greater range from the surface of the device.
Ideally, a diagnostic test should require minimal processing of the biological sample prior to detection of the analyte of interest. However, non-specific adsorption of proteins in complex biological samples, a process known as fouling, significantly decreases the sensitivity of label-free devices due to a lack of biological specificity at the sensor surface. Common strategies for passivating surfaces to non-specific biological interactions include adsorption of ‘blocking’ proteins (e.g., serum albumin) and grafting inert polymeric scaffolds (e.g., polyethylene glycol) to the surface that increase surface hydration through intermolecular hydrogen bonding. These passivation strategies are only partially effective and are inadequate to fully resist protein fouling in complex biological samples.
One biological system of great interest is the typing of blood. Immediate bloody typing is not presently enabled by any simple, portable technologies. Blood typing is necessary for personalized treatment of wounds (e.g., in combat situations) and improved safety in blood banking.